Rare and common genetic variations in the Keap1/Nrf2 antioxidant response pathway impact thyroglobulin gene expression and circulating levels, respectively

Matana, Antonela; Ziros, Panos G.; Chartoumpekis, Dionysios V.; Renaud, Cédric O; Polašek, Ozren; Hayward, Caroline; Zemunik, Tatijana; Sykiotis, Gerasimos P.

doi:10.1016/j.bcp.2019.08.007

Cited by 17 publications

(12 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings suggest that loss of Nrf2 function might play an important role in the development of diabetes. In agreement with this notion, GWAS analysis uncovered several mutations in the Nrf2 pathway that are associated with T2D (Jimenez-Osorio et al, 2016;Matana et al, 2020;Wang et al, 2015b). Recently, we found that Nrf2 stimulates β-cell proliferation in both rat insulinoma INS-1 cells and in primary pancreatic human islets (Kumar et al, 2018).…”

Section: Introductionsupporting

confidence: 74%

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Baumel-Alterzon

Brill

et al. 2021

Preprint

View full text Add to dashboard Cite

Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation and mass. Depletion of Nrf2 in β-cells resulted in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and β-cell mass. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding β-cell mass in diabetes.

show abstract

Section: Introductionsupporting

confidence: 74%

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Baumel-Alterzon

Brill

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…The dysfunction of the NRF2 by SNPs is gradually becoming a milestone to discern disease development and progression in diabetes [ 29 ]. The presence of SNPs in the regulatory motifs of NRF2 gene would affect the efficient binding of transcription factors to the gene and consequently repress transcription [ 30 ]. The present study analyzed the NRF2 SNP rs35652124 (g.178130073 C/T, c.-214 G>A), in T2DM and DFU subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative Medicine and Cellular Longevity transcription [30]. The present study analyzed the NRF2 SNP rs35652124 (g.178130073 C/T, c.-214 G>A), in T2DM and DFU subjects.…”

mentioning

confidence: 98%

Genetic Polymorphism of the Nrf2 Promoter Region (rs35652124) Is Associated with the Risk of Diabetic Foot Ulcers

Rajan

Umapathy

Ali

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

The genetic polymorphism in the nuclear factor erythroid 2-related factor 2 (Nrf2) gene has been reported as one of the prognosis markers for various diseases, including cancer. Nrf2 is a key transcription factor involved in wound healing by regulating angiogenesis. We investigated the genetic association of NRF2 single-nucleotide polymorphism rs35652124 with T2DM and DFU and assessed its functional impact. A total of 400 subjects were recruited for the study and categorized into three groups: infected DFU patients (DFU, n=100), T2DM patients without complications (T2DM, n=150), and healthy adults with normal glucose tolerance (NGT, n=150). The subjects were genotyped by PCR-RFLP, and the polymorphism was identified by bidirectional Sanger sequencing. The expression of NRF2, IL-10, TNF-α, and IL-6 was studied by qPCR to evaluate the functional impact of rs35652124. The “TT” genotype of rs35652124 was associated with a significant risk for T2DM [OR=2.2 (1.2-4.2), p=0.01] and DFU [OR=7.9 (4-14.9), p<0.0001]. A significant decrease in transcriptional levels of NRF2 and IL-10 and a remarkable increase in TNF-α and IL-6 were observed in subjects with TT genotype. In conclusion, rs35652124 (TT) is a harmful genetic variant that predisposes to insulin resistance and impaired angiogenesis. Hence, it may serve as a diagnostic genetic marker for T2DM and DFU in combination with different inflammatory markers.

show abstract

“…Nrf2 accumulates and enters the nucleus and induces its target genes via specific binding sequences called antioxidant response elements (AREs). In the last few years, a role of Nrf2 in thyroid physiology and pathophysiology has emerged [ 7 ]; Nrf2 upregulates Tg transcription [ 2 ] through AREs in a Tg enhancer [ 2 , 8 ], downregulates Tg iodination [ 2 ], and is activated in response to iodide exposure [ 2 , 9 ], as well as in thyroid carcinomas [ 10 , 11 , 12 ]. The Nrf2 pathway is of high medical interest due to its druggable nature, and Nrf2 inducers have been tested in clinical trials for cancer chemoprevention, chronic kidney disease, neurodegenerative diseases, and diabetes [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Chartoumpekis

Ziros

Georgakopoulos-Soares

et al. 2020

Antioxidants

Self Cite

View full text Add to dashboard Cite

Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC.

show abstract

Rare and common genetic variations in the Keap1/Nrf2 antioxidant response pathway impact thyroglobulin gene expression and circulating levels, respectively

Cited by 17 publications

References 60 publications

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Nrf2 Regulates β-cell Mass by Suppressing Cell Death and Promoting Proliferation

Genetic Polymorphism of the Nrf2 Promoter Region (rs35652124) Is Associated with the Risk of Diabetic Foot Ulcers

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Contact Info

Product

Resources

About